bims-unfpre 2022-03-20 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2022‒03‒20
ten papers selected by
Susan Logue
University of Manitoba

Activation of the UPR sensor ATF6α is regulated by its redox-dependent dimerization and ER retention by ERp18.
Endoplasmic reticulum-unfolded protein response pathway modulates the cellular response to mitochondrial proteotoxic stress.
A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPRER axis.
The unfolded protein response transducer IRE1α promotes reticulophagy in podocytes.
Deletion of Gdf15 reduces ER stress-induced beta cell apoptosis and diabetes.
Identification of Novel Oxindole Compounds That Suppress ER Stress-Induced Cell Death as Chemical Chaperones.
Role of ER stress inhibitors in the management of diabetes.
Hyperglycemia-triggered ATF6-CHOP pathway aggravates acute inflammatory liver injury by β-catenin signaling.
GSDMD enhances cisplatin-induced apoptosis by promoting the phosphorylation of eIF2α and activating the ER-stress response.
Paracrine signal emanating from stressed cardiomyocytes aggravates inflammatory microenvironment in diabetic cardiomyopathy.

Proc Natl Acad Sci U S A. 2022 Mar 22. 119(12): e2122657119

Activation of the UPR sensor ATF6α is regulated by its redox-dependent dimerization and ER retention by ERp18.

Ojore Benedict Valentine Oka, Arvin Shedrach Pierre, Marie Anne Pringle, Wanida Tungkum, Zhenbo Cao, Bethany Fleming, Neil John Bulleid.

  SignificanceMembrane and secretory proteins are synthesized in the endoplasmic reticulum (ER). Perturbations to ER function disrupts protein folding, causing misfolded proteins to accumulate, a condition known as ER stress. Cells adapt to stress by activating the unfolded protein response (UPR), which ultimately restores proteostasis. A key player in the UPR response is ATF6α, which requires release from ER retention and modulation of its redox status during activation. Here, we report that ER stress promotes formation of a specific ATF6α dimer, which is preferentially trafficked to the Golgi for processing. We show that ERp18 regulates ATF6α by mitigating its dimerization and trafficking to the Golgi and identify redox-dependent oligomerization of ATF6α as a key mechanism regulating its function during the UPR.

Keywords:  ATF6; ER stress; proteostasis; unfolded protein response

DOI:  https://doi.org/10.1073/pnas.2122657119
Cell Stress Chaperones. 2022 Mar 16.

Endoplasmic reticulum-unfolded protein response pathway modulates the cellular response to mitochondrial proteotoxic stress.

Rajasri Sarkar, Kannan Boosi Narayana Rao, Mainak Pratim Jha, Koyeli Mapa.

  Mitochondria and endoplasmic reticulum (ER) remain closely tethered by contact sites to maintain unhindered biosynthetic, metabolic, and signalling functions. Apart from its constituent proteins, contact sites localize ER-unfolded protein response (UPR) sensors like Ire1 and PERK, indicating the importance of ER-mitochondria communication during stress. In the mitochondrial sub-compartment-specific proteotoxic model of yeast, Saccharomyces cerevisiae, we show that an intact ER-UPR pathway is important in stress tolerance of mitochondrial intermembrane space (IMS) proteotoxic stress, while disrupting the pathway is beneficial during matrix stress. Deletion of IRE1 and HAC1 leads to accumulation of misfolding-prone proteins in mitochondrial IMS indicating the importance of intact ER-UPR pathway in enduring mitochondrial IMS proteotoxic stresses. Although localized proteotoxic stress within mitochondrial IMS does not induce ER-UPR, its artificial activation helps cells to better withstand the IMS proteotoxicity. Furthermore, overexpression of individual components of ER-mitochondria contact sites is found to be beneficial for general mitochondrial proteotoxic stress, in an Ire1-Hac1-independent manner.

Keywords:  ER stress; ER-mitochondria contact sites; Mito-UPR; Protein homeostasis; Proteotoxic stress; Unfolded protein response

DOI:  https://doi.org/10.1007/s12192-022-01264-2
Cell Death Differ. 2022 Mar 17.

A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPRER axis.

Yuanyuan Yan, Miao He, Lin Zhao, Huizhe Wu, Yanyun Zhao, Li Han, Binbin Wei, Dongman Ye, Xuemei Lv, Yan Wang, Weifan Yao, Haishan Zhao, Bo Chen, Zining Jin, Jian Wen, Yan Zhu, Tao Yu, Feng Jin, Minjie Wei.

Hypoxic tumor microenvironment (TME) plays critical roles in induction of cancer stem cell-like phenotype in breast cancer and contribute to chemoresistance. However, the mechanism underlying stemness reprogramming of breast cancer cells (BCs) by hypoxic TME remains largely unknown. In the present study, we illustrated that HIF-2α, but not HIF-1α, induces stemness in BCs under hypoxia through SOD2-mtROS-PDI/GRP78-UPRER pathway, linking mitochondrial metabolic state to endoplasmic reticulum (ER) response via mitochondrial reactive oxygen species (mtROS) level. HIF-2α activates endoplasmic reticulum unfolded protein response (UPRER) in drug-sensitive MCF7 and T47D cells to induce drug-resistant stem-like phenotype. Genetic depletion or pharmacological inhibition (YQ-0629) of HIF-2α abolished hypoxia-induced stem-like phenotype in vitro and in vivo. Mechanistically, HIF-2α activates transcription of superoxide dismutase 2 (SOD2) under hypoxia and thereby decreases mtROS level. With less mtROS transported to endoplasmic reticulum, the expression and activity of protein disulfide isomerase (PDI) is suppressed, allowing glucose-regulated protein 78 (GRP78) to dissociate from receptor proteins of UPRER and bind misfolded protein to activate UPRER, which eventually confer chemoresistance and stem-like properties to BCs. Moreover, the increase in mtROS and PDI levels caused by HIF-2α knockdown and the subsequent UPRER inhibition could be substantially rescued by mitoTEMPOL (a mtROS scavenger), 16F16 (a PDI inhibitor), or GRP78 overexpression. Overall, we reported the critical roles of HIF-2α-SOD2-mtROS-PDI/GRP78-UPRER axis in mediating hypoxia-induced stemness in BCs, highlighting the interaction between organelles and providing evidence for further development of targeted HIF-2α inhibitor as a promising therapeutic strategy for chemoresistant breast cancer.

DOI: https://doi.org/10.1038/s41418-022-00963-8
Biochim Biophys Acta Mol Basis Dis. 2022 Mar 15. pii: S0925-4439(22)00054-0. [Epub ahead of print] 166391

The unfolded protein response transducer IRE1α promotes reticulophagy in podocytes.

José R Navarro-Betancourt, Joan Papillon, Julie Guillemette, Chen-Fang Chung, Takao Iwawaki, Andrey V Cybulsky.

  Glomerular diseases involving podocyte/glomerular epithelial cell (GEC) injury feature protein misfolding and endoplasmic reticulum (ER) stress. Inositol-requiring enzyme 1α (IRE1α) mediates chaperone production and autophagy during ER stress. We examined the role of IRE1α in selective autophagy of the ER (reticulophagy). Control and IRE1α knockout (KO) GECs were incubated with tunicamycin to induce ER stress and subjected to proteomic analysis. This showed IRE1α-dependent upregulation of secretory pathway mediators, including the coat protein complex II component Sec23B. Tunicamycin enhanced expression of Sec23B and the reticulophagy adaptor reticulon-3-long (RTN3L) in control, but not IRE1α KO GECs. Knockdown of Sec23B reduced autophagosome formation in response to ER stress. Tunicamycin stimulated colocalization of autophagosomes with Sec23B and RTN3L in an IRE1α-dependent manner. Similarly, during ER stress, glomerular α5 collagen IV colocalized with RTN3L and autophagosomes. Degradation of RTN3L and collagen IV increased in response to tunicamycin, and the turnover was blocked by deletion of IRE1α; thus, the IRE1α pathway promotes RTN3L-mediated reticulophagy and collagen IV may be an IRE1α-dependent reticulophagy substrate. In experimental glomerulonephritis, expression of Sec23B, RTN3L, and LC3-II increased in glomeruli of control mice, but not in podocyte-specific IRE1α KO littermates. In conclusion, during ER stress, IRE1α redirects a subset of Sec23B-positive vesicles to deliver RTN3L-coated ER fragments to autophagosomes. Reticulophagy is a novel outcome of the IRE1α pathway in podocytes and may play a cytoprotective role in glomerular diseases.

Keywords:  Autophagy; Collagen IV; ERphagy; Endoplasmic reticulum stress; Reticulon-3; Sec23B

DOI:  https://doi.org/10.1016/j.bbadis.2022.166391
Endocrinology. 2022 Mar 15. pii: bqac030. [Epub ahead of print]

Deletion of Gdf15 reduces ER stress-induced beta cell apoptosis and diabetes.

Guanlan Xu, Junqin Chen, Seong Ho Jo, Truman B Grayson, Sasanka Ramanadham, Akio Koizumi, Emily L Germain-Lee, Se-Jin Lee, Anath Shalev.

  Endoplasmic reticulum (ER) stress contributes to pancreatic beta cell apoptosis in diabetes, but the factors involved are still not fully elucidated. Growth differentiation factor 15 (GDF15) is a stress response gene and has been reported to be increased and play an important role in various diseases. However, the role of GDF15 in beta cells in the context of ER stress and diabetes is still unclear. In this study, we have discovered that GDF15 promotes ER stress-induced beta cell apoptosis and that downregulation of GDF15 has beneficial effects on beta cell survival in diabetes. Specifically, we found that GDF15 is induced by ER stress in beta cells and human islets, and that the transcription factor C/EBPβ is involved in this process. Interestingly, ER stress-induced apoptosis was significantly reduced in INS-1 cells with Gdf15 knockdown and in isolated Gdf15 knockout mouse islets. In vivo, we found that Gdf15 deletion attenuates streptozotocin-induced diabetes by preserving beta cells and insulin levels. Moreover, deletion of Gdf15 significantly delayed diabetes development in spontaneous ER stress-prone Akita mice. Thus, our findings suggest that GDF15 contributes to ER stress-induced beta cell apoptosis and that inhibition of GDF15 may represent a novel strategy to promote beta cell survival and treat diabetes.

Keywords:  Beta cells; Diabetes; ER stress; apoptosis and GDF15

DOI:  https://doi.org/10.1210/endocr/bqac030
ACS Chem Neurosci. 2022 Mar 16.

Identification of Novel Oxindole Compounds That Suppress ER Stress-Induced Cell Death as Chemical Chaperones.

Yuto Hasegawa, Masanari Motoyama, Akie Hamamoto, Shintaro Kimura, Yuji O Kamatari, Hiroaki Kamishina, Kentaro Oh-Hashi, Kyoji Furuta, Yoko Hirata.

  Endoplasmic reticulum (ER) stress and oxidative stress lead to protein misfolding, and the resulting accumulation of protein aggregates is often associated with the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and prion disease. Small molecules preventing these pathogenic processes may be effective interventions for such neurodegenerative disorders. In this paper, we identify several novel oxindole compounds that can prevent ER stress- and oxidative stress-induced cell death. Among them, derivatives of the lead compound GIF-0726-r in which a hydrogen atom at the oxindole ring 5 position is substituted with a methyl (GIF-0852-r), bromine (GIF-0854-r), or nitro (GIF-0856-r) group potently suppressed global ER stress. Furthermore, GIF-0854-r and -0856-r prevented protein aggregate accumulation in vitro and in cultured hippocampal HT22 neuronal cells, indicating that these two compounds function effectively as chemical chaperones. In addition, GIF-0852-r, -0854-r, and -0856-r prevented glutamate-induced oxytosis and erastin-induced ferroptosis. Collectively, these results suggest that the novel oxindole compounds GIF-0854-r and -0856-r may be useful therapeutics against protein-misfolding diseases as well as valuable research tools for studying the molecular mechanisms of ER and oxidative stress.

Keywords:  ER stress; chemical chaperone; ferroptosis; oxindole; oxytosis

DOI:  https://doi.org/10.1021/acschemneuro.2c00064
Eur J Pharmacol. 2022 Mar 12. pii: S0014-2999(22)00154-6. [Epub ahead of print] 174893

Role of ER stress inhibitors in the management of diabetes.

Krishna Prasad M, Sundhar Mohandas, Kunka Mohanram Ramkumar.

  Endoplasmic Reticulum (ER) stress has been established to play a key pathophysiological role in developing metabolic diseases such as Diabetes Mellitus (DM). The complications of DM have been closely associated with deregulation of the unfolded protein response (UPR) signaling pathways, which are critically responsible for restoring homeostasis following ER stress. Chronic ER stress in the background of persistent hyperglycemia, as observed in DM, overwhelms the UPR signaling and commits the cells to apoptosis. The factors such as hyperglycemia, increased reactive oxygen species (ROS), disrupted calcium homeostasis, and overt inflammation serves as major UPR signal transduction pathways, including PKR like ER kinase (PERK), Activating transcription factor 6α/β (ATF6), and Inositol requiring enzyme1α/β (IRE1). The constantly developing understanding of these ER stress mediators has also unraveled their potential as therapeutic targets of small molecules termed ER stress inhibitors. A wide range of both naturally occurring and synthetic compounds have been screened and studied for their properties to inhibit ER stress in various experimental models. This review article elucidates the critical signaling pathways associated with response to ER stress. We shed light on the crosstalk between ER stress mediators with oxidative and inflammatory stress mediators in the background of DM. We extensively summarize the pieces of evidence sourced from preclinical and clinical research about the role of ER stress inhibitors and their pharmacological mechanism of action in alleviating ER stress in diabetes.

Keywords:  Chaperones; Diabetes mellitus; ER stress Inhibitors; Endoplasmic reticulum stress; Therapeutic target; UPR

DOI:  https://doi.org/10.1016/j.ejphar.2022.174893
Cell Death Discov. 2022 Mar 14. 8(1): 115

Hyperglycemia-triggered ATF6-CHOP pathway aggravates acute inflammatory liver injury by β-catenin signaling.

Chao Yang, Zeng Wang, Yuanchang Hu, Shikun Yang, Feng Cheng, Jianhua Rao, Xuehao Wang.

Although hyperglycemia has been documented as an unfavorable element that can further induce liver ischemia-reperfusion injury (IRI), the related molecular mechanisms remain to be clearly elaborated. This study investigated the effective manner of endoplasmic reticulum (ER) stress signaling in hyperglycemia-exacerbated liver IRI. Here we demonstrated that in the liver tissues and Kupffer cells (KCs) of DM patients and STZ-induced hyperglycemic mice, the ER stress-ATF6-CHOP signaling pathway is activated. TLR4-mediated pro-inflammatory activation was greatly attenuated by the addition of 4-phenylbutyrate (PBA), one common ER stress inhibitor. The liver IRI in hyperglycemic mice was also significantly reduced after PBA treatment. In addition, deficiency of CHOP (CHOP-/-) obviously alleviates the hepatic IRI, and pro-inflammatory effects deteriorated by hyperglycemia. In hyperglycemic mice, β-catenin expression was suppressed while the ATF6-CHOP signal was activated. In the liver tissues of PBA-treated or CHOP-/- hyperglycemic mice, the expression of β-catenin was restored. Furthermore, CHOP deficiency can induce protection against hyperglycemia-related liver IRI, which was disrupted by the knockdown of β-catenin will cause this protection to disappear. High glucose (HG) treatment stimulated ATF6-CHOP signaling, reduced cellular β-catenin accumulation, and promoted the TLR4-related inflammation of BMDMs. But the above effects were partially rescued in BMDMs with CHOP deficiency or by PBA treatment. In BMDMs cultured in HG conditions, the anti-inflammatory functions of CHOP-/- were destroyed by the knockdown of β-catenin. Finally, chimeric mice carrying WT or CHOP-/- BMDMs by bone marrow transplantation were adopted to verify the above conclusion. The current study suggested that hyperglycemia could trigger ER stress-ATF6-CHOP axis, inhibit β-catenin activation, accelerate inflammation, and deteriorate liver IRI, thus providing the treatment potential for management of sterile liver inflammation in DM patients.

DOI: https://doi.org/10.1038/s41420-022-00910-z
Cell Death Discov. 2022 Mar 14. 8(1): 114

GSDMD enhances cisplatin-induced apoptosis by promoting the phosphorylation of eIF2α and activating the ER-stress response.

Qianyu Zhang, Zixian Huang, Xi Rui, Yan Wang, Yongqiang Wang, Yuwei Zhou, Rui Chen, Yongju Chen, Yuepeng Wang, Shihao Li, Haigang Li, Ximing Shen, Yancan Liang, Yin Zhang, Zhiquan Huang.

GSDMD is the key effector of pyroptosis, but its non-pyroptosis-related functions have seldom been reported. Here, we report that GSDMD is overexpressed in different types of tumours, including head and neck squamous-cell carcinoma, and it promotes the sensitivity of tumour cells to cisplatin. Unexpectedly, the enhanced cisplatin sensitivity is mediated by apoptosis but not pyroptosis, the well-known function of GSDMD. Furthermore, we found that GSDMD can activate the unfolded protein response by promoting the phosphorylation of eIF2α. Mechanistically, we demonstrated that GSDMD can directly bind to eIF2α and enhance the interaction between eIF2α and its upstream kinase PERK, leading to eIF2α phosphorylation. Consequently, the protein levels of ATF-4 were upregulated, downstream apoptosis-related proteins such as CHOP were activated, and apoptosis was induced. Remarkably, activation of endoplasmic-reticulum (ER) stress induced by GSDMD promotes cell apoptosis during cisplatin chemotherapy, thereby increasing the treatment sensitivity of tumours. Therefore, for the first time, our work reveals an unreported nonpyroptotic function of the classic pyroptosis protein GSDMD: it promotes cell apoptosis during cisplatin chemotherapy by inducing eIF2α phosphorylation and ER stress, which are related to the drug sensitivity of tumours. Our study also indicated that GSDMD might serve as a biomarker for cisplatin sensitivity.

DOI: https://doi.org/10.1038/s41420-022-00915-8
iScience. 2022 Mar 18. 25(3): 103973

Paracrine signal emanating from stressed cardiomyocytes aggravates inflammatory microenvironment in diabetic cardiomyopathy.

Namrita Kaur, Andrea Ruiz-Velasco, Rida Raja, Gareth Howell, Jessica M Miller, Riham R E Abouleisa, Qinghui Ou, Kimberly Mace, Susanne S Hille, Norbert Frey, Pablo Binder, Craig P Smith, Helene Fachim, Handrean Soran, Eileithyia Swanton, Tamer M A Mohamed, Oliver J Müller, Xin Wang, Jonathan Chernoff, Elizabeth J Cartwright, Wei Liu.

  Myocardial inflammation contributes to cardiomyopathy in diabetic patients through incompletely defined underlying mechanisms. In both human and time-course experimental samples, diabetic hearts exhibited abnormal ER, with a maladaptive shift over time in rodents. Furthermore, as a cardiac ER dysfunction model, mice with cardiac-specific p21-activated kinase 2 (PAK2) deletion exhibited heightened myocardial inflammatory response in diabetes. Mechanistically, maladaptive ER stress-induced CCAAT/enhancer-binding protein homologous protein (CHOP) is a novel transcriptional regulator of cardiac high-mobility group box-1 (HMGB1). Cardiac stress-induced release of HMGB1 facilitates M1 macrophage polarization, aggravating myocardial inflammation. Therapeutically, sequestering the extracellular HMGB1 using glycyrrhizin conferred cardioprotection through its anti-inflammatory action. Our findings also indicated that an intact cardiac ER function and protective effects of the antidiabetic drug interdependently attenuated the cardiac inflammation-induced dysfunction. Collectively, we introduce an ER stress-mediated cardiomyocyte-macrophage link, altering the macrophage response, thereby providing insight into therapeutic prospects for diabetes-associated cardiac dysfunction.

Keywords:  Biological sciences; Cardiovascular medicine; Cell biology; Immunology

DOI:  https://doi.org/10.1016/j.isci.2022.103973